Acylated derivatives of 1, 2, 3, 4-tetrahydro-1-oxo-beta-carbolines



United States Patent 3,364,224 ACYLATED DERIVATIVES 0F 1,2,3,4-TETRA- HYDRO-l-OXO-fi-CARBOLINES John Shavel, Jr., Mendham, Maximilian von Strandtmann, Rockaway Township, and Marvin P. Cohen, New Milford, N.J., assignors to Warner-Lambert Pharmaceutical Company, Morris Plains, N.J., a corporation of Delaware No Drawing. Original application June 27, 1961, Ser. No. 119,831, now Patent No. 3,182,071, dated May 4, 1965. Divided and this application Sept. 28, 1964, Ser. No.

9 Claims. (31. 260-295) ABSTRACT OF THE DISCLOSURE The present invention relates to new and novel acylated indole derivatives having the formula:

RI R i I T wherein the i Rr-C in which n is 0 to 3 and R; which may be in the ortho, meta or para-position is phenyl, halogen, lower alkyl, trifluoromethyl, lower alkoxy, hydrogen, di-(lower alkyl) amino, cycloalkyl, nitro, benzoyl and the acyl radical of an aliphatic carboxylic acid containing 2 to 6 carbon atoms; A is a radical of the formula in which R R, and R are hydrogen, lower alkyl, or

in which in is O to 3; R and R are hydrogen, lower alkyl, cycloalkyl, lower alkyl substituted with a hydroxy, amino or lower alkoxy group, radicals of the formula in which is O to 3, and when taken with the amino nitrogen atom form a piperidino, pyrrolidino or morpholino group, and when R is hydrogen, R may be benzoyl or the acyl radical of an aliphatic carboxylic acid containing 2 to 6 carbon atoms; and R is hydrogen, carboxy or carbo-lower alkoxy. This invention also relates to the pharmaceutically acceptable non-toxic acid addition and quaternary ammonium salts of the above compounds, to a method of preparing them and to new and novel intermediates obtained in the course of the synthesis.

The present application is a divisional-application of copending US. patent application Ser. No. 119,831 filed June 27, 1961, and now US. Patent No. 3,182,071 granted May 4, 1965.

As used throughout the specification and in the claims, the following terms have the following meanings: lower alkyl and lower alkoxy refer to straight and branched chain aliphatic groups containing 1 to 6 carbon atoms; cycloalkyl refers to cyclic aliphatic groups containing 5 to 7 carbon atoms; and halogen refers to chlorine, bromine or fluorine.

The compounds of our invention are indole derivatives bearing a side chain at the 3-position containing an amino nitrogen atom and an acyl group at the 4, 5, 6 or 7 position. The substitution of an acyl group on the benzene ring of the indole structure to form compounds of the above formula has not heretofore been known and is an important feature of our invention.

The new and novel compounds of our invention are valuable intermediates useful in the preparation of other indole derivatives. For example, the presence of an substituent renders our compounds susceptible to the various reactions of ketones involving a carbonyl group. In addition, our compounds have been found to possess interesting and significant pharmacological activity. They have a pronounced lowering effect upon blood pressure, with an ability to increase coronary flow, and also exhibit antiserotonin activity and depress the central nervous system. Those compounds of our invention having the formula 0 ll lower alicyi-C CHr-CHr-NH: N

are unusually effective hypotensive agents which promote an increase in coronary flow and also exhibit anti-serotonin activity.

It has now been found that those compounds of our invention having the formula:

wherein R and A are as described hereinabove and where the substituent is at the 4, 5, or 6 position may be prepared by the following sequence:

First, a diazonium compound having the formula:

3 Rl I X NEN+ wherein the i R -C- substituent is meta or para to the nitrogen atom and X is halogen or hydroxyl is reacted with a substituted cyclic nitrogen-containing acid of the formula:

wherein M is hydrogen or an alkali metal to form a hydrazone of the formula:

by heating with formic acid or a mineral acid, such as hydrochloric acid. Refluxing the above heterocyclic substituted indole derivative in the presence of aqueous alcoholic alkali, for example, potassium or sodium hydroxide in aqueous ethanol, followed by acidification yields the desired compounds of the formula:

wherein the substituent is at the 4, or 6 position.

Those compounds of our invention of the formula:

may be prepared by a modification of the foregoing procedure wherein the carbonyl group of the 'o RH'L substituent is protected as a group during the sequence. The

DH Batmgroup may be regenerated to an either at the end of the sequence or at' the heterocyclic substituted indole stage by an oxidation procedure, such as the Well-known Oppenauer Oxidation, which involves treatment under reflux with an aluminum alkoxide, such a 4 as aluminum phenoxide, aluminum isopropoxide, aluminum t-butoXide and the like and a ketone such as cyclohexanone or acetone in an inert organic solvent such as benzene, toluene and the like.

In addition, those compounds of our invention having the formula:

may alternately be prepared by treating the known compound l,2,3,4-tetrahydro-1-oXo-B-carboline, described in German Patent 1,082,598, with an acyl halide of the for mula O Bri l-X where X is halogen, or an acid anhydride of the formula (silo in the presence of a Friedel-Crafts catalyst to form a 6-acyl-1,2,3,4-tetrahydro-l-oxo-fi-carboline of the for: mula:

0 ML m NH 7 H u r Y which may be hydrolyzed as described above to form a 5-acyl-Z-carboxytryptarnine. The acylation of 1,2,3,4- tetrahydro-l-oxo-/3-carboline is described and claimed. in copending application of John Shave], Jr., entitled Meth- 0d of Preparing 6-Acylated Derivatives of 1,2,3,4-tetrahydro-l-oxo-B-Carboline, filed concurrently herewith.

Refiuxing the acylated 2-carboxy substituted indole derivatives of the formula:

in which the Rat- ' substituent is at the 4, 5, 6 or 7 positionin an acid medium, for example a mixture of acetic and: hydrochloric acids, followed by basification, results in decarboxylation to form those compounds of our invention having the formula: v

' which compounds may in turn be N-acylated by conventional procedures to form compounds of the formula: l

ii Rr-C in which R is phenyl or lower alkyl.

When 2-carboxy substituted indole derivatives of the formula:

are decarboxylated as described above, it is observed that a cyclic intermediate having the formula:

may be isolated from the reaction mixture. These cycloauhydro compounds have been observed to be the more stable forms of the 4-acylated indole derivatives of our invention having the formula:

IFA-NH:

The acylated Z-carboxy substituted indole derivatives of our invention may be treated with formaldehyde in the presence of palladium on charcoal or with a mixture of formaldehyde and formic acid to form compounds of the formula:

CH; 5 A N I ll ooon which may then be decarboxylated as described above to form compounds of the formula:

/CHa O AN R1-C CH3 Those compounds of our invention having the formula:

AN\ RI C R1 g C O O-lower alkyl are prepared by the following sequence, as described and claimed in copending application of John Shavel, Jr., and Maximilian von Strandtmann entitled Method of Preparing Substituted Indole Derivatives, Ser. No. 119,830, filed June 27, 1961.

First, a keto ester of the formula:

u R t CH:

om-C-on CO O-lower alkyl is coupled with a diazonium compound of the formula:

u Ri-C Y- NEN+ wherein Y is halogen or hydroxyl to form a hydrazone of the formula:

I C O O-lower alkyl Then, the above hydrazone is heated with formic acid or a mineral acid to yield those compounds of our invention having the formula:

It has been found that these compounds may be hydrolyzed and decarboxylated by treatment with an acid under reflux to yield compounds of the formula:

The compounds of our invention may be converted into their pharmaceutically acceptable nontoxic acid addition and quaternary ammonium salts by conventional procedures. Exemplary of nontoxic acid addition salts are those formed with maleic, furmaric, succinic, tartaric, citric, malic, cinnamic, sulfonic, hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids. The acid addition salts may be prepared in the conventional manner, by treating a solution or suspension of the free base in an organic solvent with the desired acid, and then recovering the salt which forms by crystallization techniques. The quaternary salts are prepared by heating a suspension of the free base in a solvent with a reactive halide such as methyl iodide, ethyl bromide, n-hexyl bromide, benzyl chloride or a reactive ester such as methyl sulfate, ethyl sulfate or methyl p-toluene sulfonate.

For therapeutic use, our compounds, either as the free base or in the form of salts, may be combined with conventional pharmaceutical diluents and carriers to form such dosage units as tablets, capsules, suppositories, elixirs, solutions .or suspensions.

The following Examples are included in order further to illustrate the present invention:

EXAMPLE 1 6-acetyl-1,2,3,4-1etrahydr0-1-ox0-fl-carboline A suspension of 69 g. of 2,3-piperidinedione-3-(pacetylphenyl)hydrazone in 345 ml. 88% formic acid is refluxed for 4 hours. After cooling, 37 g. of precipitated material is filtered off and dried in vacuo over P 0 An additional 13 g. of material is obtained by dilution of the filtrate with several volumes of water. Yield: 50 g. (78% of theory) M.P. 367-372". Recrystallization from glacial acetic acid yields pure 6-acetyl-1,2,3,4-tetrahydro-1-oxofi-car-boline, M.P. 370-372.

Analysis.-Calcd.: C, 68.40; H, 5.30; N, 12.27, Found: C, 68.35; H, 5.33; N, 12.08.

EXAMPLE 2 6-acetyl-3-methyl-1,2,3,4-tetrahydr0-1-0x0-p-carb0line A suspension of 78 g. of 6-methyl-2,3-piperdinedione 3-(p-acetylphenyl)hydrazone in 390 ml. 88% formic acid is refluxed for 4 hours. After cooling, the precipitated material is filtered off and dried in vacuo over P 0 Yield: 57 g. (78% of theory) M.P. 355-61". Recrystallization from 88% formic acid yields pure 6-acetyl-3- 7 methyl-1,2,3,4-tetrahydro-l-oxo-fl-carboline, M.P. 358- 60.

Analysis.-Calcd.: C, 69.40; H, 5.82; N, 11.56,. Found: C, 69.55; H, 5.94; N, 11.40.

EXAMPLE 3 6-acetyl-4-methyl-1,2,3,4-tetrahydro-1-0x0-B-carb0line A suspension of 9 g. of methyl-2,3-piperidinedione- 3-(p-acetylphenyl)hydrazone in ml. 88% formic acid is refluxed for 4 hours. The solution is concentrated to half of its volume and the concentrate is diluted with two volumes of water. The precipitated yellow product is filtered 01f, washed with water, and dried in vacuo over P 0 Yield: 5 g. of theory) M.P. 330-40. Recrystallization from absolute ethanol yields pure 6-acetyl- 4-methyl-1,2,3,4-tetrahydro-l-oxo-B-carboline, M.P. 360- Analysis.Ca1cd.: C, 69.40; H, 5.82; N, 11.56. Found: C, 69.63; H, 5.88; N, 11.40.

A suspension of 54 g. of 2,3-piperidinedione-3.-(ppropionylphenyl)hydrazone in 270 ml. of 88% formic acid is refluxed for 4 hours. After cooling 41 g. of precipitated material are filtered oil and dried in vacuo over P 0 An additional 5 g. of material are obtained by concentrating the filtrate to about one third of its volume in vacuo, and diluting the concentrate with twice its volume of water. Yield: 46 g. of theory) M.P. 345-53".Recrystallization from 88% formic acid yields 6 propionyl-l,2,3,4-tetrahydro-1-oxo-p-carboline, M.P.

Analysis.--Calcd.: C, 69.40; H, 5.82; N, 11.56. Found:

c, 69.00;'H, 5.97;,N, 11.28.

i EXAMPLE 5 V A suspension of .11 g. of 5-methyl-2,3-piperidinedione- 3-(p-propionylphenyl)hydrazone in 55 ml; 88% formic acid is refluxed for four hours. After cooling 5.5 g. of

V precipitated material. is filtered off and dried in vacuo over P H An additional 3.8 g. of material is obtained by centrated to a very small volume to remove most of the formic acid and diluted with several volumes of water.

' V The heavy precipitate formed is filtered ofi, washed with some cold water, and dried in vacuo over P 0 at room temperature. Yield: 19.5 g. (92.5% of theory) M.P. 270- 282". Recrystallization from ,ethanol yields pure 6-' benzoyl-l,2,3,4-tetrahydro-1-oxo-fi-carboline, M.P. 284- Analysis.Calcd.: C, 74.46; H, 4.86; N, 9.65. Found: C, 74.59; H, 4.92; N, 9.61.

7 8 EXAMPLES 7-8 5 -acetyl-1 ,2,3 ,4 -tetrahydr0-1 -0x0-;8-carboline and 7 acetyl-1,2,3,4-tetrahydr0-I -0x0-fl-carboline A suspension of 34g. of 2,3-piperidinedione-3-(macetylphenyl)hydrazone in 170 ml. 88% formic acid is refluxed for 4 hours. The solution is concentrated to about half its volume under vacuo, and diluted with ml. of

water. An oil precipitates out which solidifies on standing. The solids are filtered off, washed with cold water, and

dried in vacuo over P 0 Yield: 26 g. (81% of theory),

M.P. 205-40. The isomeric mixture is separated by fractional crystallization from absolute ethanol. The less soluble isomer which is 7-acetyl-1,2,3,4-tetrahydro-l-oxo- ,B-carboline has a melting point of 283-86".

Analysis.Calcd.: C, 68.40; H, 5.30; N, 12.27. Found:

C, 68.30; H, 5.38; N, 12.45.

The more soluble isomer which is S-acetyl-l-oxo- 1,2,3,4-tetrahydro-fl-carboline has a melting point of 241-43".

Analysis.-Found: C, 68.62; H, 5.48; N, 12.06.

In the foregoing examples, all temperatures are given in degrees centigrade.

It is understood that the foregoing detailed description is given merely by way of illustration and that many variations may be made therein without-departing from the spirit of our invention.

What is claimed is:

1. Compounds of the formula:

W V A Rr-C i i wherein R is a member selected from the group consisting of lower alkyl and phenyl A is selected from the group consisting of CHa \GH-CH1 \CH2 I and OH? on, CHCH;

lower alkyl and radicals of the formula in which m is 0 to 3.

2. 6-acetyl-,1,2,3,4-tetrahydro-l-oxo-fi-carboline.

line.

4. 6 acetyl4-methyl-1,2,3,4-tetrahydro-l-oxo-p-carboline.

5. 6-propionyl-1,2,3,4-tetrahydro-l-oxo-B-carboline.

6. 4-methyl 6 propionyl-1,2,3,4-tetrahydro-l-oXo-B- carboline.

7. 6-benzoyl-1,2,3,4-tetrahydro-l-oxo-fl-carboline.

8. 5-acetyl-l,2,3,4-tetrahydro-l-oxo-B-carboline.

9. 7-acetyl-1,2,3,4-tetrahydro-l-oxo-fi-carboline..

References Cited UNITED STATES PATENTS 2,888,451 '5/1959 'Heneck-a et a1. 260-296 3,294,809 12/1966 Shavel 260 -296 65 JOHN D. RANDOLPH, Primary Examiner.

A. L. ROTMAN, Assistant Examiner.

3. 6-acetyl-3-methyl-1,2,3,4-tetrahydro-l-oxo-B-carbo- 

